Current studies concentrate on elucidating the physiology and clinical relevance of peptide neurohormones (e.g., corticotropin releasing factor) which influence both central nervous system function and pituitary-adrenal regulation. In volunteers, continuous infusion of ovine CRF (oCRF) produces moderate hypercortisolism associated with a phase advance in the circadian rhythms of ACTH and cortisol, analogous to that seen naturalistically in depression. Continuous ACTH infusion to volunteers produces cortisol responses similar to those seen in Cushing's disease. Analysis of ACTH and cortisol responses to oCRF in depression and Cushing's disease supports the hypothesis of excessive endogenous CRF secretion in depression and autonomous corticrotropin cell ACTH overproduction in Cushing's disease. The CRF test can distinguish depression from even mild Cushing's disease with 95% accuracy when the ACTH/cortisol ratios obtained during CRF testing are compared. The CRF stimulation test is also an aid in the differential diagnosis of adrenal insufficiency and in distinguishing Cushing's disease from ectopic ACTH secretion. The responses to CRF testing in patients with anorexia nervosa and primary anxiety disorder suggest that the pathophysiology of hypercortisolism in the disorders is similar to that of depression. Comparisons of the pharmacokinetics and biological effects of oCRF and human CRF (hCRF) in primates and volunteers show that the two peptides are equally potent in releasing ACTH, however, the metabolic clearance rate of hCRF is ten times faster than that of oCRF. hCRF pulses given to volunteers and patients with hypothalamic CRF deficiency produce ACTH pulses whose duration and amplitude mimic endogenous secretory episodes. In the sheep, stress (i.e., insulin-induced hypoglycemia or benzodiazepine superantagonist administration) causes a significant rise in ACTH in association with a rise in CSF CRF.